Previously, we reported that synthetic viral fusion peptides with sequences homologous to those of human immunodeficiency virus (HIV) and herpes simplex virus, when conjugated to another peptide serving as reporter or anti-viral drug, can enter cells susceptible to infection by their corresponding viruses. These fusion peptides, like the viruses, require specific receptors for entry into the target cells. The fusion peptide from the envelope glycoprotein of HIV-1, gp41, can only enter cells expressing chemokine receptors. The present project is an attempt to utilize the fusion peptide?s ability to recognize this particular receptor and convert it into a blocker that can prevent cellar entry by HIV. Anti-HIV drugs currently in use, whether they interfere with HIV replication such as the protease and reverse transcriptase inhibitors or disrupt the fusion process such as AMD3100 and T-20 peptide analogs, invariably encounter the evolvement of resistant HIV strains. The present approach is designed to block the patient?s own door (the receptor) to deny access to HIV instead of trying to compete with the ever-mutating virus. A compound that is being tested on HeLa cells is a fusion peptide with a valine residue replaced by a glutamate residue. It has been shown that this substitution renders the virus incapable of infecting target cells, but the peptide appears to bind to the cell membrane. We found that indeed this modified peptide was unable to penetrate HeLa cells. However, experiments to test its membrane-binding ability were inconclusive?most likely due to weak interaction. We are now testing another peptide that links the fusion peptide to a short segment located near the T-21 peptide of gp41. This particular sequence may be responsible for anchoring gp41 to the cell membrane prior to the formation of coiled-coils involving both T-20 and T-21 helices. Another approach is to conjugate the fusion peptide, possibly through a linker peptide, to chemokine receptor inhibitors like AMD3100 that binds to a region interacting with go120. The project will be done in collaboration with Dr. Kefeng Qin who is conducting HIV research at the University of Maryland Medical School.